近日，加拿大麦吉尔大学Judith N. Mandl及其小组发现，DOCK8缺失通过迁移引起的细胞破碎导致2型偏向的辅助性T细胞反应。相关论文于2020年10月5日在线发表在《自然—免疫学》杂志上。
Title: Migration-induced cell shattering due to DOCK8 deficiency causes a type 2–biased helper T cell response
Author: Caitlin Schneider, Connie Shen, Angelica A. Gopal, Todd Douglas, Benjamin Forestell, Keith D. Kauffman, Dakota Rogers, Patricio Artusa, Qian Zhang, Huie Jing, Alexandra F. Freeman, Daniel L. Barber, Irah L. King, Maya Saleh, Paul W. Wiseman, Helen C. Su, Judith N. Mandl
Abstract: Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations in DOCK8, a guanine exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans, Dock8−/− mice have a profound type 2 CD4+ helper T (TH2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-TH2 stimuli. We found that recruited Dock8−/−CX3CR1+ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1β that drives granulocyte−macrophage colony-stimulating factor (GM-CSF) production by CD4+ T cells. Blocking IL-1β, GM-CSF or caspase activation eliminated the type-2 skew in mice lacking Dock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and TH2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4+ T cell responses in allergic disease. Humans with inherited defects in DOCK8 expression are prone to allergic, type 2 CD4+ T cell responses. Mandl and colleagues reveal an important role for cell death in driving such type 2 signals during infection.